Measurement Properties of Patient-Reported Outcome Measures for Adolescent and Young Adult Survivors of a Central Nervous System Tumor: A Systematic Review

Purpose: To identify and evaluate patient-reported outcome measures (PROMs) for assessing survivorship-related concepts for adolescent and young adult (AYA) survivors of central nervous system (CNS) tumors. Methods: We searched five electronic databases. Two researchers independently screened all titles for inclusion and used consensus-based standards for the selection of health measurement instruments (COSMIN) guidance to grade the quality of evidence for each measurement property. Results: Four studies met eligibility criteria: single-item pain thermometer; single-item fatigue thermometer; 37-item pediatric functional assessment of cancer therapy—brain tumor survivors, measuring quality of life; and 12-item Perceived Barriers Scale to assess barriers to employment. The Perceived Barrier Scale showed high-quality evidence for internal consistency and moderate quality evidence for construct and structural validity. Evidence for the measurement properties of the other PROMs was low-to-moderate quality. Conclusion: We found one PROM with sufficient evidence for good measurement properties to support its use. This warrants development and evaluation of further PROMs to inform ongoing supportive care for this population. Implications for Cancer Survivors: The Perceived Barriers Scale is sufficiently validated and could be considered to guide support for AYA survivors of CNS tumors to achieve their employment goals.


Background
C entral nervous system (CNS) tumors account for one in five childhood cancers and up to 15% of adolescent and young adult (AYA) cancers.The term AYA is commonly defined as the period between 15 and 39 years. 1 This age range spans a period of rapid physical, cognitive, and emotional growth distinct from childhood and adulthood where individuals become independent, reach their educational and employment goals, and form lasting relationships. 2 Immature decision-making skills, with a drive for independence, make this a unique group, with cancer during this stage disrupting the usual pattern of development with the potential to impact their future lives.Lastly, young people experience greater challenges than older patients with cancer. 3he AYA age range coincides with the highest rate of survival of CNS tumors. 4Increasing number of child and AYA CNS tumor survivors means a large proportion of patients under follow-up for CNS tumors falls within the AYA age range. 5urvivors of a CNS tumor are particularly at risk compared with survivors of other cancers due to the direct effect tumors can have on personality, behavior, cognition, and memory.][8] The large majority of young CNS tumor survivors experience at least one ongoing symptom, 9 and more than half experience life-altering and long-term disability. 10This negatively impacts their social well-being, ability to attain developmental milestones, rates of marriage and employment, and their health-related quality of life (HRQOL). 9,11,12ong-term follow-up services for CNS tumor survivors aim to reduce treatment sequelae and maximize opportunities to return to ''normality'' and reintegration into society as quickly as possible. 13There is increasing demand for individualized follow-up care for survivors of cancer and support with self-managing their symptoms. 14,15Currently, a medical model of care is still the most common method of follow-up in the United Kingdom and United States. 16This model tends to rate clinical care (checking for signs and symptoms of late effects) as more important than supportive care that orientates toward lifestyle advice and reintegration into education. 17This means many AYA CNS survivors may receive care that does not fully address their ongoing needs.
][20] It can also improve symptom management, overall HRQOL, and patient satisfaction with care in people with cancer. 21,22Although the routine use of PROMs in oncology settings in the United Kingdom is expanding, it is not yet standard. 18,23,24As a result, opportunities to identify relevant patient issues, provide individualized care, and improve HRQOL are missed.
PROMs must have clinical utility, while also being valid, reliable, relevant, and acceptable to the population in which they are used. 257][28][29][30] In addition to age-specific considerations, PROMs for use with survivors of a CNS tumor may require design features to decrease cognitive demand and account for cognitive and neurological disabilities, for example, by reducing complexity of items or using images instead of text. 31 previous review examining the use of PROMs in CNS tumor survivors identified studies in populations with a mean age >39 years, 32 whereas reviews of PROMs focusing on pediatric CNS tumor survivors only included two studies wherein 15-18-year olds were included or wherein the mean age was between 9.5 and 13.7 years. 6,33These reviews also concluded that all PROMs required further evaluation of construct validity, internal consistency, and responsiveness to change.Therefore, it remains unclear which high-quality PROMs are available for the AYA CNS tumor population.

Aim and Objectives
We explore to what extent there are PROMs available for measuring health and survivorship-related concepts in AYA survivors of CNS tumors.Ultimately, this will contribute to facilitating and improving the delivery of individualized supportive follow-up care for this patient population.
The specific objectives of our review were: (1) Identify studies reporting the development and evaluation of PROMs to assess health and survivorshiprelated concepts in AYA CNS tumor survivors.
(2) For each PROM identified under 1: a. describe what concept it is designed to measure, b. describe its characteristics, c. assess its measurement properties, and d. describe its interpretability, clinical utility, and feasibility.

Methods
We followed the 10 steps to conducting a systematic review of PROMs as proposed by the COnsensus based Standards for selection of health Measurement INstruments (COSMIN). 34To address objective 1, and in accordance with this guidance, steps 1-4 included formulation of the aim, formulation of eligibility criteria, literature search, and select abstracts and full text articles.For objective 2, steps 5-9 of the guidance were specific to evaluating the measurement properties of the PROM.
These steps include evaluation of content validity, evaluation of internal structure (structural validity and internal consistency), evaluation of remaining measurement properties (crosscultural validity, reliability, measurement error, criterion validity, hypothesis testing for construct validity, and responsiveness), evaluate interpretability and feasibility, and formulate recommendations.The final step was to report the systematic review in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidance. 35The study protocol was registered on the International Prospective Register of Systematic Reviews (PROS-PERO; ID: 343426).No ethical approval was required to conduct this review.

Search strategy
We searched five electronic databases, including MED-LINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Web of Science.The research team comprised clinical experts in the clinical specialty, experts in PROM development and evaluation, and a clinical librarian.Together, they developed the search strategy described in Table 1, incorporating terms for CNS tumors, survivors of cancer, and the PROM filter as recommended by the COSMIN guidance. 34In addition, the research team added search terms related to already known AYA-specific PROMs (e.g., cancer needs questionnaire) 36 to further enable identification of evaluation studies in AYA CNS populations.We only included studies published in English without restriction of publication date.
To complement our electronic search, we manually searched reference lists of included studies, and conducted a targeted search in MEDLINE for any included PROMs or for comparator instruments used in their evaluation.
Eligibility criteria are described in Table 2.

Study selection
After removing duplicates, two researchers (K.L. and E.H.) independently screened all studies using systematic review software (RAYYAN) 38 to record decisions.They screened all studies by title and abstract in stage 1 against the eligibility criteria (Table 2) and read full text articles where further information was required to decide on inclusion (stage 2).Reasons for exclusion were only recorded for stage 2. Any disagreements were resolved through discussion with a third member of the research team (S.N.V.D.V.).

Data extraction
Two researchers (K.L. and E.H.) independently extracted the following data items in duplicate, resolving disagreements through discussion: PROM: construct, number and type of factors/domains, mode of administration, recall period, number of items, response options, interpretation of scoring, and language.Study population: sample size, age, gender, ethnicity, disease type, treatment, time since treatment, and country.Information on the methods and findings of evaluating the following measurement properties: structural validity, internal consistency, cross-cultural validity, reliability, measurement error (limits of agreement), criterion validity (correlation with gold standard), hypothesis testing, and responsiveness.Clinical utility and interpretability of the PROM (missing items, floor and ceiling effects, and minimal important change or minimal important difference) and its feasibility (completion time, required mental ability to complete PROM (e.g., reading age), ease of score calculation, and study setting).

Assessing the quality of studies and evidence for measurement properties
We used the COSMIN Risk of Bias Checklist to assess the methodological quality of studies for each measurement property reported.The overall score for each study was the lowest score applied to any assessed subelement and rated as very good, adequate, doubtful, inadequate, and not applicable (N/A). 39We then rated the result of each study on a measurement property (except content validity and PROM development) against the COSMIN criteria for good measurement properties as sufficient (+), insufficient (-), and indeterminate (?).
We qualitatively described interpretability and feasibility data.Where results from different studies on one measurement property could be pooled, we would conduct a metaanalysis.Lastly, we used the grading of recommendations assessment, development, and evaluation to determine the quality of evidence for each measurement property. 40

Results
After excluding duplicate titles, we screened 1486 titles and abstracts, reading the full text for 44 articles.Four studies describing four PROMs met the eligibility criteria and were evaluated and appraised in the analysis (Fig. 1).Searching reference lists of the full text articles identified a further three studies.
We excluded 17 PROMs validation studies after full text screening because they did not meet our population criteria, these are given in Table 3.
Included study and PROM characteristics We included the following four PROMs: (1) Single item screening tool for fatigue (fatigue thermometer). 572) Single item screening tool for pain (pain thermometer).37 The scope of this research does not include evaluating the responses of proxy reports.
CNS, central nervous system; HRQOL, health-related quality of life; PROM, patient-reported outcome measures.

PATIENT-REPORTED OUTCOME MEASURES AND CANCER SURVIVORS
(3) 12-item Perceived Barriers Scale for young people (18-30 years) to assess barriers to career development and employment. 59(4) 37-item quality-of-life measure (pediatric functional assessment of cancer therapy in brain tumor survivors; pediatric functional assessment of cancer therapychildhood brain tumor survivors [PedsFACT-BrS]). 60e fatigue thermometer is commonly used in adult ambulatory clinics and the purpose of the study was to evaluate its use in the AYA CNS survivor population.Similarly, the pain thermometer is commonly used in children over the age of 8 years and the purpose of the study was to evaluate its use in the AYA CNS survivor population.Strauser et al. 59 reported the development and validation of the Perceived Barriers Scale and Yoo et al. 60 reported the validation of the PedsFACT-BrS in Korean AYA CNS survivors.Table 4 describes the PROM characteristics, as well as the characteristics of the populations in which they were developed and/or validated.All studies reported information regarding the number of items and domains where relevant.
Although there was equal representation of gender identity, ethnic diversity was limited with Caucasian participants forming a majority.Chordas et al. 58 and Strauser et al. 59 reported participants being approached in person during clinic visit or by mail, and Yoo et al. 60 and Brand et al. 57 reported completion of the instruments during a clinic visit.In all studies, information was lacking on whether the PROMs were completed electronically or on paper.

PROM measurement properties
Table 5 gives an overview of which measurement properties had been assessed for each PROM, and for each measurement property a summary of the methodological quality, the application of the criteria for good measurement properties, and the quality of evidence.Supplementary Data S1-S3 contains further details regarding the risk of bias assessment underlying our decisions on methodological quality given in Table 5.
The most common measurement property evaluated for all four PROMs was hypothesis testing for construct validity: that is, testing the assumption that the PROM validly measures the construct it aims to assess.We graded the quality of evidence for this measurement property in all studies as low, except for the Perceived Barrier Scale, where it was moderate.As each PROM was measuring a different construct, it was not possible to perform a meta-analysis.We graded the quality of evidence for internal consistency of the Perceived Barriers Scale and PedsFACT-BrS as high and moderate, respectively, with both instruments demonstrating good correlation between items.Lastly, Strauser et al. 59 reported PROM development in collaboration with users and health professionals, suggesting content validity of the Perceived Barriers Scale.
Risk of bias in PROM development and content validity is assessed using COSMIN checklist though data are not analyzed and given a score on methodological quality.Information regarding the development of the Perceived Barriers Scale included interviews with patients and health care professionals to maximize comprehensiveness and content validity. 59The translated PedsFACT-BrS was also pretested with young people to assess comprehensiveness. 60espite content validity being considered the most important measurement property, 39 limited information as reported in these articles meant much of the checklist could not be completed and no other published studies were found to report on the development of the PROMs.

PROM interpretability, clinical utility, and feasibility
Information on interpretability or clinical utility was lacking in all studies.Regarding feasibility, all studies except   Measurement properties rated as sufficient (+), insufficient (-), indeterminate (?).
b Per PROM, there was only one evaluation per measurement property, ''inconsistency'' did not apply.We, therefore, used the modified GRADE approach to grade the quality of evidence.
As the sample size was only one participant below the recommended threshold of 100 for downgrading, we did not downgrade Chordas et al.COSMIN, consensus-based standards for the selection of health measurement instruments; GRADE, the grading of recommendations of assessment, development, and evaluation.
Strauser et al. 59 reported information on missing data.Yoo et al. 60 reported that they imputed missing data using the mean score for the scale or subscale where data were missing and no >20% of items within a subscale were missing.Chordas et al. 58 and Brand et al. 57 excluded incomplete data sets from their analysis.
No studies reported floor/ceiling effects or information on what they considered a minimal important difference for their PROM.Data collection for all instruments happened in the follow-up clinic setting or through mailshot, but only Yoo et al. 60 reported the time taken to complete the instrument (15-20 minutes).Supplementary Data S3 provides further details on what studies reported on PROM interpretability, clinical utility, and feasibility.

Discussion
Our review identified four PROMs developed and evaluated to assess survivor-related concepts in AYA CNS tumor survivors.The Perceived Barriers Scale had moderate-tohigh quality evidence for sufficient internal consistency and structural and construct validity.This PROM may, therefore, be suitable for use in AYA CNS survivors, and could help patients to achieve their employment goals and contribute to increasing their (currently low) rates of employment. 61,62The study evaluating the PedsFACT-BrS found that the qualityof-life instrument had sufficient internal consistency, reliability, and construct and known group validity.
However, the quality of the underlying evidence for these measurement properties was low to moderate, warranting further evaluation studies before the PedsFACT-BrS can be recommended for use in practice for this specific population.
AYA CNS tumor survivors often experience multiple long-term conditions that affect their independence and HRQOL.Once further evidence for sufficient measurement properties is available, the PedsFACT-BrS, or similar instruments, could facilitate monitoring of HRQOL and inform follow-up services to optimize HRQOL.The two single-item screening tools (i.e., the fatigue thermometer and the pain thermometer) had low-quality evidence for insufficient measurement properties and can, therefore, not be recommended for use.Lastly, future research should assess cross-cultural validity, measurement error, and responsiveness, which were not evaluated in any of the studies.This is in keeping with findings from other PROM reviews in adult 32 and pediatric CNS cancer populations. 6,33he COSMIN guidance advises only including studies wherein at least 50% of participants meet the eligibility criteria for the review.To adhere to this guidance, we excluded several PROM validation studies wherein at least half of their study population did not consist of AYA CNS survivors, or, wherein insufficient information to assess the population characteristics was reported.Lack of such information hampers making robust recommendations on whether a PROM is suitable for this group.This is supported by multiple studies highlighting that PROMs data can be inaccurate or inadequate if the PROM does not contain relevant age-appropriate domains representative of the target disease population 26,[63][64][65][66][67] Researchers should, therefore, report complete and sufficiently detailed information about the age and conditions of their study population.This will help maximize the utility of future research on PROMs for AYAs with a specific type of cancer, particularly since individual studies for this group are typically relatively small.In addition, detailed population characteristics facilitate assessing indirectness when grading the quality of evidence.For example, for Yoo et al., 60 the mean age of participants met our population inclusion criteria but the reported age range suggested that their study participants might not fully reflect our target population.

Limitations
There is a risk of publication bias in our review because PROMs evaluation studies reporting negative results may not have been published.This means we may have missed studies of PROMs for this unique population.In addition, there may be language bias as we only included publications in English.
We complemented our search terms with the names of PROMs that we knew were available for mixed AYA cancer populations.PROMs not known to our multidisciplinary research team were, therefore, less likely to be picked up by our search strategy.
Lastly, our review aimed to identify PROMs measuring any construct, despite COSMIN advising a PROMs review to ideally focus on one construct only. 39It is well known that survivors of CNS tumors may experience multiple ongoing issues, and any validated PROM could be used in follow-up services to enhance the support offered.Combined with the anticipated scarcity of PROMs studies for AYA CNS tumor survivors, we, therefore, deemed it appropriate to include all constructs in one review.

Implications for clinical practice and research
9][70] The implementation of tools that identify ongoing issues is advocated and would facilitate provision of personalized follow-up, 14,15 as well as clinical audits and service evaluations. 71However, the routine use of such tools is still largely lacking in follow-up services.
This review suggests that services could consider the Perceived Barriers Scale to identify barriers to employment and identify and address individual needs.However, for this PROM to support audit and service evaluation, further research should examine its reliability and responsiveness to change.The PedsFACT-BrS also showed several sufficient measurement properties for evaluating HRQOL in this population, but further research should strengthen the current evidence base, while also evaluating the instrument's responsiveness to change.
The use of reliable tools can allow future research to examine the effectiveness of interventions designed to lessen unmet needs by measuring and quantifying changes.Future studies may also focus on evaluating PROMs for AYA survivors of CNS tumors that were originally developed and validated in populations with mixed cancer types or older/younger populations.
Lastly, given that a PROM can measure any aspect of survivorship and survivors of a CNS tumor experience many ongoing symptoms, it must be acknowledged that we are at risk of burdening patients with multiple PROMs designed to measure different aspects of survivorship.Furthermore, some may perceive the use of PROMs as impersonal and negatively impacting the patient-clinician relationship. 72TIENT-REPORTED OUTCOME MEASURES AND CANCER SURVIVORS Future research may, therefore, also consider examining the preference of how young people would like unmet needs to be assessed and how they can be used without detriment to the patient-professional relationship.

Conclusion
We found four PROMs for assessing survivorship-related concepts in AYA survivors of CNS tumors, but only the Perceived Barriers Scale had sufficient quality evidence for its measurement properties.In the absence of any other validated instruments to assess barriers to employment, this scale could be considered for use in practice, although further research is necessary to evaluate its reliability and responsiveness to change.Our review warrants development and evaluation of additional PROMs to inform supportive care for this population if we are to address the complex ongoing sequelae and provide personalized support directed to those AYA survivors of CNS tumors in need.

FIG. 1 .
FIG. 1. PRISMA flowchart of the screening and inclusion process (last search: May 2022).PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyse.

Table 2 .
Inclusion and Exclusion Criteria

Table 3 .
Validation Studies: Reason for Exclusion PedsFACT-BrS, pediatric functional assessment of cancer therapychildhood brain tumor survivors; PedsQL, pediatric quality of life; PROMIS, patient reported outcome measurement information system; SF-SUNS, short-form survivor unmet needs survey; SD, standard deviation; TYA, teenage and young adult.

Table 4 .
Patient-Reported Outcome Measures Characteristics and Study Population Characteristics

Table 5 .
Summary of Methodological Quality and Strength of the Evidence for Each Patient-Reported Outcome Measure Property a